The neurology of carbonic anhydrase type II deficiency syndrome
The neurology of carbonic anhydrase type II deficiency syndrome
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DOI：
10.1093/brain/awr302
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发表时间：
2011-12-01
期刊：
影响因子：
14.5
通讯作者：
Abu-Amero, Khaled K.
中科院分区：
文献类型：
--
作者：
Bosley, Thomas M.;Salih, Mustafa A.;Abu-Amero, Khaled K.
II型碳酸氢酶缺乏综合征是一种罕见的常染色体隐性遗传病，其基本特征包括骨化症、肾小管性酸中毒和脑钙化。我们描述了来自10个无关血缘家庭的23个个体(男性10人，女性13人，终检年龄2~29岁)的神经学、眼科和神经放射学特征，这些人是由于内含子2剪接位点纯合突变(阿拉伯突变)而导致的II型碳酸氢酶缺乏症。所有患者均有骨质疏松症、肾小管性酸中毒、发育迟缓、身材矮小、头面部比例失调、大颅顶、宽额头等表现。大约三分之二的人存在智力低下，从轻度到重度不等。除了一名深部肌腱反射活跃的患者和两名严重精神发育迟滞和痉挛四肢瘫痪的患者外，一般神经检查并不明显。视球和视网膜正常，但视神经受累23/46只眼，其严重程度不同，发生随机，与视神经管狭窄程度有统计学相关性。除两名患者眼球运动部分受限外，眼球运动完全正常。两名患者存在眼球跳动异常，其中一半患者有感觉性或调节性斜视，七名患者有先天性眼球震颤。这些异常最常见的是与传入障碍有关，但这种障碍的一个微小的脑干成分仍然是可能的。所有内耳道大小正常，没有患者有明显的临床听力损失。对18例患者进行了神经成像，并重复了长达10年的时间。脑钙化一般呈进行性发展，分布明显，主要累及基底节和丘脑，额部灰白质交界处多于后部。至少有一名儿童在9岁时没有脑钙化，这表明在儿童时期碳酸二型脱水酶缺乏综合征中可能并不总是存在脑钙化。脑钙化、认知障碍和视神经受累的变异性可能意味着影响疾病进程的额外遗传或表观遗传影响。然而，在这组患者中，这种疾病的总体表型没有以前报道的那么严重，这增加了早期使用碳酸氢盐治疗全身性酸中毒的可能性，这可能是这种罕见的常染色体隐性问题的转归的关键。
Carbonic anhydrase type II deficiency syndrome is an uncommon autosomal recessive disease with cardinal features including osteopetrosis, renal tubular acidosis and brain calcifications. We describe the neurological, neuro-ophthalmological and neuroradiological features of 23 individuals (10 males, 13 females; ages at final examination 2-29 years) from 10 unrelated consanguineous families with carbonic anhydrase type II deficiency syndrome due to homozygous intron 2 splice site mutation (the 'Arabic mutation'). All patients had osteopetrosis, renal tubular acidosis, developmental delay, short stature and craniofacial disproportion with large cranial vault and broad forehead. Mental retardation was present in approximately two-thirds and varied from mild to severe. General neurological examinations were unremarkable except for one patient with brisk deep tendon reflexes and two with severe mental retardation and spastic quadriparesis. Globes and retinae were normal, but optic nerve involvement was present in 23/46 eyes and was variable in severity, random in occurrence and statistically correlated with degree of optic canal narrowing. Ocular motility was full except for partial ductional limitations in two individuals. Saccadic abnormalities were present in two, while half of these patients had sensory or accommodative strabismus, and seven had congenital nystagmus. These abnormalities were most commonly associated with afferent disturbances, but a minor brainstem component to this disorder remains possible. All internal auditory canals were normal in size, and no patient had clinically significant hearing loss. Neuroimaging was performed in 18 patients and repeated over as long as 10 years. Brain calcification was generally progressive and followed a distinct distribution, involving predominantly basal ganglia and thalami and grey-white matter junction in frontal regions more than posterior regions. At least one child had no brain calcification at age 9 years, indicating that brain calcification may not always be present in carbonic anhydrase type II deficiency syndrome during childhood. Variability of brain calcification, cognitive disturbance and optic nerve involvement may imply additional genetic or epigenetic influences affecting the course of the disease. However, the overall phenotype of the disorder in this group of patients was somewhat less severe than reported previously, raising the possibility that early treatment of systemic acidosis with bicarbonate may be crucial in the outcome of this uncommon autosomal recessive problem.